Pancreatic Polypeptide-Fold Peptide Receptors and Angiotensin II–Induced Renal Vasoconstriction

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Abstract
The Gipathway augments renal vasoconstriction induced by angiotensin II in spontaneously hypertensive but not normotensive Wistar-Kyoto rats. Because the Gi-coupled pancreatic polypeptide (PP)-fold peptide receptors Y1and Y2are expressed in kidneys and are activated by endogenous PP-fold peptides, we tested the hypothesis that these receptors regulate angiotensin II-induced renal vasoconstriction in kidneys from hypertensive but not normotensive rats. A selective Y1-receptor agonist [(Leu31,Pro34)-neuropeptide Y; 6 to 10 nmol/L] greatly potentiated angiotensin II–induced changes in perfusion pressure in isolated, perfused kidneys from hypertensive but not normotensive rats. A selective Y2-receptor agonist (peptide YY3-36; 6 nM) only slightly potentiated angiotensin II–induced renal vasoconstriction and only in kidneys from hypertensive rats. Neither the Y1-receptor nor the Y2-receptor agonist increased basal perfusion pressure. BIBP3226 (1 μmol/L, highly selective Y1-receptor antagonist) and BIIE0246 (1 μmol/L, highly selective Y2-receptor antagonist) completely abolished potentiation by (Leu31,Pro34)-neuropeptide Y and peptide YY3-36, respectively. Y1-receptor and Y2-receptor mRNA and protein levels were expressed in renal microvessels and whole kidneys, but the abundance was similar in kidneys from hypertensive and normotensive rats. Both Y1-receptor–induced and Y2-receptor–induced potentiation of angiotensin II–mediated renal vasoconstriction was completely abolished by pretreatment with pertussis toxin (30 μg/kg IV, blocks Giproteins). These data indicate that, in kidneys from genetically hypertensive but not normotensive rats, Y1-receptor activation markedly enhances angiotensin II–mediated renal vasoconstriction by a mechanism involving Gi. Although Y2receptors can also potentiate angiotensin II–mediated renal vasoconstriction via Gi, the effect is modest compared with Y1receptors. These findings may have important implications for the etiology of genetic hypertension.